Blood purification device and method for producing same

ABSTRACT

A blood purification device includes a porous molded body containing an inorganic ion-adsorbing material and is characterized by the following: the concentrations of Mg, Al, Ti, V, Cr, Mn, Fe, Ni, Cu, Zn, Ga, Rb, Sr, Y, Zr, Mo, Ru, Ag, Cd, Sn, Cs, La, Pr, Sm, Gd, Tb, Ta, Au, Tl, Co, In, and Bi are each 0.1 ppb or less and the concentrations of Ba, Nd, Pb, And Ce are each 1 ppb or less in a physiological saline solution for injection both three months and six months after said physiological saline solution for injection is sealed in the blood purification device; and the number of fine particles having a size of 10 μm or more is 25 or less and the number of fine particles having a size of 25 μm or more is 3 or less in 1 mL of the physiological saline solution for injection.

FIELD

The present invention relates to a blood purification device comprisinga porous molded body that contains an inorganic ion adsorbent, and amethod for producing it. More specifically, the invention relates to ablood purification device comprising a porous molded body that containsan inorganic ion adsorbent, which has high phosphorus adsorptioncapacity and can be safely used, as well as to a method for producingit.

BACKGROUND

Healthy adults with normally functioning kidneys discharge excessphosphorous out of the body primarily through urine. However, kidneydisease patients with impaired renal function, such as chronic renalfailure patients, are unable to properly excrete excess phosphorus outof the body, and this leads to gradual internal buildup of phosphorus,causing the condition of hyperphosphatemia.

Persistent hyperphosphatemia can lead to secondary hyperparathyroidism,resulting in renal osteopathy with symptoms such as painful and fragileor deformed bones that are prone to fracture, while in cases ofconcomitant hypercalcemia, the risk of cardiac failure due tocalcification of the cardiovascular system also increases.

Cardiovascular calcification is one of the most serious complications ofchronic renal failure, and proper control of phosphorus levels in thebody is extremely important to prevent hyperphosphatemia in chronicrenal failure patients.

For hemodialysis patients, phosphorus that has accumulated in the bodyis periodically removed and regulated by dialysis treatment byhemodialysis, hemofiltration dialysis or hemofiltration so thathyperphosphatemia does not result. Dialysis treatment usually needs tobe carried out three times per week, with a treatment period of 4 hourseach time.

However, when a hemodialysis patient ingests the 1000 mg of phosphorusthat is ingested per day by a healthy person, the amount of phosphorusthat would normally be excreted from the kidneys (650 mg) accumulates inthe body, reaching an accumulated amount of 4550 mg within a week.Normal hemodialysis can remove about 800 to 1000 mg of phosphorus with asingle dialysis procedure, allowing removal of about 3000 mg ofphosphorus by dialysis 3 times a week. Since the amount of phosphorusthat can be removed by dialysis treatment (3000 mg) does not match theamount of phosphorus that accumulates each week (4550 mg), accumulationof phosphorus in the body occurs as a result.

Maintenance dialysis patients who are chronic renal failure patientshave lost renal function as the major route of phosphorus excretion, andtherefore the function of excreting phosphorus into the urine isessentially lost. Since phosphorus is not present in the dialysate fromdialysis treatment it is possible to remove phosphorus from the body bydiffusion into the dialysate, but at the current time it is not possibleto achieve adequate excretion with the currently employed dialysis timesand dialysis conditions.

The phosphorus-removal effect of dialysis treatment alone is thereforeinadequate, and consequently alimentary therapies and drug therapieswith ingestion of phosphorus adsorbents are also used in addition todialysis treatment to achieve phosphorus control, although it isimportant that consumption of phosphorus is restricted after havingevaluated the nutritional status of the patient and confirmed that thereis no malnutrition.

The CKD-MBD (chronic kidney disease-bone mineral metabolism disorder)guidelines for phosphorus control stipulate a serum phosphorus value of3.5 to 6.0 mg/dL.

A serum phosphorus level of below 3.5 mg/dL is hypophosphatemia which isa cause of rachitis or osteomalacia, while a level of 6.0 mg/dL orhigher is hyperphosphatemia, which can lead to cardiovascularcalcification.

Alimentary therapy to lower phosphorus consumption also depends on thenutritional status of the patient, while the preferences of the patientmust also be taken into account, and therefore management of bodyphosphorus concentrations with alimentary therapy can be difficult.

Some drug therapies exist that are oral phosphorus adsorbents that canbind with dietary phosphate ion in the gastrointestinal tract to forminsoluble phosphates, and that are taken either before or during mealsto inhibit absorption of phosphorus through the intestinal tract, thusmanaging phosphorus concentrations. However, a very large amount ofphosphorus adsorbent must be taken before meals for such drug therapy.This results in a high probability of side-effects when a phosphorusadsorbent is taken, such as vomiting, feeling of fullness, constipationor drug buildup in the body, such that the compliance is extremely low(often said to be 50% or lower), and therefore management of phosphorusconcentrations by drugs can be problematic for both doctors andpatients.

PTL 1 discloses circulating a dialysis composition containing aphosphorus adsorbent in dialysate during hemodialysis treatment toefficiently remove phosphorus in blood without direct contact of thephosphorus adsorbent with the blood.

Also, PTL 2 discloses a hemodialysis system wherein a phosphorusadsorbent comprising a polycationic polymer is provided separately fromthe hemodialyzer, whereby phosphorus accumulated in the blood is removedthrough the route of blood outside the body.

PTL 3 discloses a porous molded body suited as an adsorbent that canrapidly remove phosphorus and other components by adsorption.

However, these blood purification devices of the prior art have lowadsorption capacity for phosphorus, and have also been insufficient interms of safe usability.

CITATION LIST Patent Literature

-   [PTL 1] International Patent Publication No. WO2011/125758-   [PTL 2] Japanese Unexamined Patent Publication No. 2002-102335-   [PTL 3] Japanese Patent Publication No. 4671419

SUMMARY Technical Problem

In light of these problems of the prior art, it is an object of thepresent invention to provide a blood purification device comprising aporous molded body, which has high phosphorus adsorption capacity andsafe usability.

Solution to Problem

As a result of repeated experimentation with the aim of solving theproblems described above, the present inventors have completed thisinvention upon finding that it is possible to provide a bloodpurification device having a high phosphorus clearance value and safeusability, by adding an inorganic ion adsorbent with high phosphorusadsorption capacity to a porous molded body, while washing with asupercritical fluid or subcritical fluid to completely remove themicroparticles and trace metals generated by the blood purificationdevice comprising the porous molded body.

Specifically, the present invention provides the following.

A blood purification device comprising a porous molded body thatincludes an inorganic ion adsorbent, wherein the concentrations of Mg,Al, Ti, V, Cr, Mn, Fe, Ni, Cu, Zn, Ga, Rb, Sr, Y, Zr, Mo, Ru, Ag, Cd,Sn, Cs, La, Pr, Sm, Gd, Tb, Ta, Au, Tl, Co, In and Bi are all 0.1 ppb orlower and the concentrations of Ba, Nd, Pb and Ce are all 1 ppb orlower, in physiological saline for injection in the blood purificationdevice at 3 months and 6 months after opening the physiological salinefor injection, while the number of microparticles with sizes of 10 μm orgreater is no more than 25 and the number of microparticles with sizesof 25 μm or greater is no more than 3, in 1 mL of the physiologicalsaline for injection at 3 months and 6 months after the samephysiological saline for injection has been encapsulated in the bloodpurification device.

Advantageous Effects of Invention

The blood purification device of the invention has high phosphorusadsorption capacity and safe usability.

Specifically, the blood purification device of the invention hasexcellent selectivity and adsorption for phosphorus in blood even with ahigh blood flow rate during extracorporeal circulation treatment, andcan eliminate the necessary amount of phosphorus from blood withoutaffecting other components in the blood. Moreover, because phosphorus inblood can be effectively removed by extracorporeal circulation,phosphorous levels in blood can be properly managed without taking oralphosphorus adsorbents that produce side-effects.

By using the blood purification device of the invention, phosphoruslevels in the blood of a dialysis patient can be properly managedwithout taking oral phosphorus adsorbents, or by taking only smallamounts (auxiliary usage), thus avoiding side-effects in dialysispatients.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is an overview diagram of a column flow test apparatus in a bloodpurification device according to an embodiment, with low-phosphorusserum using bovine plasma.

DESCRIPTION OF EMBODIMENTS

Embodiments of the invention will now be explained in detail.

The blood purification device of the embodiment is a blood purificationdevice comprising a porous molded body that includes an inorganic ionadsorbent, wherein the concentrations of Mg, Al, Ti, V, Cr, Mn, Fe, Ni,Cu, Zn, Ga, Rb, Sr, Y, Zr, Mo, Ru, Ag, Cd, Sn, Cs, La, Pr, Sm, Gd, Tb,Ta, Au, Tl, Co, In and Bi are all 0.1 ppb or lower and theconcentrations of Ba, Nd, Pb and Ce are all 1 ppb or lower, inphysiological saline for injection in the blood purification device at 3months and 6 months after opening the physiological saline forinjection, while the number of microparticles with sizes of 10 μm orgreater is no more than 25 and the number of microparticles with sizesof 25 μm or greater is no more than 3, in 1 mL of the physiologicalsaline for injection at 3 months and 6 months after the samephysiological saline for injection has been encapsulated in the bloodpurification device.

For safe usability, production of the blood purification device of theembodiment must ensure that the concentrations of Mg, Al, Ti, V, Cr, Mn,Fe, Ni, Cu, Zn, Ga, Rb, Sr, Y, Zr, Mo, Ru, Ag, Cd, Sn, Cs, La, Pr, Sm,Gd, Tb, Ta, Au, Tl, Co, In and Bi are all 0.1 ppb or lower and theconcentrations of Ba, Nd and Pb are all 1 ppb or lower in the salinesolution at 3 months and 6 months after the physiological saline forinjection has been encapsulated in the blood purification device. Themetal concentration in the saline solution at 3 months and 6 monthsafterwards is the difference compared to the metal concentration in thephysiological saline for injection before injection into the bloodpurification device.

[Porous Molded Body]

The porous molded body of the embodiment contains an inorganic ionadsorbent, and preferably it is composed of a porous molded body-formingpolymer, the inorganic ion adsorbent and an inorganic ion adsorbent. Inthe porous molded body, the sum of the pore volumes for pore diametersof 1 nm to 80 nm as measured by the nitrogen gas adsorption method ispreferably 0.05 cm³/g to 0.7 cm³/g per unit mass of the inorganic ionadsorbent.

For this embodiment, the sum of the pore volumes for pore diameters of 1nm to 80 nm measured by the nitrogen gas adsorption method is 0.05 cm³/gto 0.7 cm³/g, preferably 0.1 cm³/g to 0.6 cm³/g and more preferably 0.2cm³/g to 0.5 cm³/g per unit mass of the inorganic ion adsorbent.

The pore volume is obtained by measuring the freeze-dried porous moldedbody by the nitrogen gas adsorption method and calculating by the BJHmethod.

The sum Va of the pore volumes per unit mass of the inorganic ionadsorbent is determined by the following formula (7):Va=Vb/Sa×100  (7)where Vb (cm³/g) is the pore volume per unit mass of the porous moldedbody calculated for the dried porous molded body and Sa (mass %) is theloading mass of the inorganic ion adsorbent in the porous molded body.

The loading mass (mass %) Sa of the inorganic ion adsorbent in theporous molded body is determined by the following formula (8):Sa=Wb/Wa×100  (8)where Wa (g) is the mass of the porous molded body when dry and Wb (g)is the ash content mass.

The ash content is the portion remaining after the porous molded bodyhas been fired at 800° C. for 2 hours.

Since the pore volume of the porous molded body measured by the nitrogengas adsorption method is a value primarily reflecting the pore volume ofthe inorganic ion adsorbent in the porous molded body, a larger valuerepresents higher diffusion efficiency of ions into the inorganic ionadsorbent, and higher adsorption capacity.

If the sum of the pore volumes per unit mass of the inorganic ionadsorbent is smaller than 0.05 cm³/g, the pore volume of the inorganicion adsorbent will be reduced and the adsorption capacity will besignificantly lower. If the value is higher than 0.7 cm³/g, on the otherhand, the bulk density of the inorganic ion adsorbent will increase andthe viscosity of the stock solution slurry will increase, therebyhampering granulation.

For the embodiment, the area-to-weight ratio of the porous molded bodymeasured by the nitrogen gas adsorption method is preferably 50 m²/g to400 m²/g, more preferably 70 m²/g to 350 m²/g and even more preferably100 m²/g to 300 m²/g.

The area-to-weight ratio is obtained by measuring the freeze-driedporous molded body by the nitrogen gas adsorption method and calculatingby the BET method.

Since the area-to-weight ratio of the porous molded body measured by thenitrogen gas adsorption method is a value primarily reflecting thearea-to-weight ratio of the inorganic ion adsorbent in the porous moldedbody, a larger value represents a greater number of ion adsorption sitesand higher adsorption capacity.

If the area-to-weight ratio of the porous molded body is smaller than 50m²/g, the number of adsorption sites of the inorganic ion adsorbent willbe lower and the adsorption capacity will be significantly reduced. Ifthe value is higher than 400 m²/g, on the other hand, the bulk densityof the inorganic ion adsorbent will increase and the viscosity of thestock solution slurry will increase, thereby hampering granulation.

For the embodiment, the loading mass of the inorganic ion adsorbent inthe porous molded body is preferably 30 mass % to 95 mass %, morepreferably 40 mass % to 90 mass % and even more preferably 50 mass % to80 mass %.

If the loading mass is less than 30 mass %, the contact frequencybetween the ions to be adsorbed and the inorganic ion adsorbent as theadsorption substrate will tend to be insufficient, while if it isgreater than 95 mass %, the strength of the porous molded body will tendto be lacking.

The porous molded body of the embodiment preferably has a mean particlesize of 100 μm to 2500 μm and is essentially in the form of sphericalparticles, the mean particle size being preferably 150 μm to 2000 μm,more preferably 200 μm to 1500 μm and even more preferably 300 μm to1000 μm.

The porous molded body of the embodiment is preferably in the form ofspherical particles, although the spherical particles are not limited tobeing merely spherical and may also be elliptical spherical.

The mean particle size for the embodiment is the median diameter of thesphere-equivalent size determined from the angular distribution of theintensity of scattered light due to laser light diffraction, assumingthe porous molded body to be spherical.

If the mean particle size is 100 μm or greater, pressure loss will below when the porous molded body is packed into a container such as acolumn or tank, making it suitable for high-speed water treatment. Ifthe mean particle size is 2500 μm or smaller, on the other hand, thesurface area of the porous molded body can be increased when it has beenpacked into a column or tank, allowing reliable adsorption of ions evenwith high-speed liquid flow treatment.

[Inorganic Ion Adsorbent]

The inorganic ion adsorbent contained in or composing the porous moldedbody of the embodiment is an inorganic substance that exhibits an ionadsorption phenomenon or ion-exchange phenomenon.

Examples of natural inorganic ion adsorbents include mineral substancessuch as zeolite and montmorillonite.

Specific examples of mineral substances include kaolin minerals having asingle layer lattice with aluminosilicates, muscovite, glauconite,kanuma soil, pyrophyllite and talc having a 2-layer lattice structure,and feldspar, zeolite and montmorillonite having a three-dimensionalframe structure.

Examples of synthetic-based inorganic ion adsorbents include metaloxides, polyvalent metal salts and insoluble hydrous oxides. Metaloxides include complex metal oxides, composite metal hydroxides andmetal hydrous oxides.

From the viewpoint of adsorption performance for the target ofadsorption, and especially phosphorus, the inorganic ion adsorbentpreferably contains at least one metal oxide represented by thefollowing formula (1):MN_(x)O_(n) ·mH₂O  (1){where x is 0 to 3, n is 1 to 4, m is 0 to 6, and M and N are metalelements selected from the group consisting of Ti, Zr, Sn, Sc, Y, La,Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Al, Si, Cr, Co, Ga,Fe, Mn, Ni, V, Ge, Nb and Ta, and are different from each other}.

The metal oxide may be a non-water-containing (non-hydrated) metal oxidewhere m in formula (1) is 0, or it may be a water-containing metal oxide(hydrated metal oxide) wherein m is a numerical value other than 0.

A metal oxide where x in formula (1) is a numerical value other than 0is a complex metal oxide represented by the chemical formula in whicheach metal element is evenly distributed in a regular manner throughoutall of the oxides, and the compositional ratio of the metal elements inthe metal oxide is constant.

Specific ones include nickel ferrite (NiFe₂O₄) or hydrous ferrite ofzirconium (Zr·Fe₂O₄·mH₂O, where m is 0.5 to 6), which form a perovskitestructure or spinel structure.

The inorganic ion adsorbent may also contain more than one type of metaloxide represented by formula (1).

From the viewpoint of excellent adsorption performance for components tobe adsorbed, and especially phosphorus, a metal oxide as the inorganicion adsorbent is preferably selected from among the following groups (a)to (c):

-   -   (a) hydrated titanium oxide, hydrated zirconium oxide, hydrated        tin oxide, hydrated cerium oxide, hydrated lanthanum oxide and        hydrated yttrium oxide,    -   (b) complex metal oxides comprising at least one metal element        selected from the group consisting of titanium, zirconium, tin,        cerium, lanthanum, neodymium and yttrium and at least one metal        element selected from the group consisting of aluminum, silicon        and iron, and    -   (c) activated alumina.

It may be a material selected from among any of groups (a) to (c), ormaterials selected from among any of groups (a) to (c) may be used incombination, or materials of each of groups (a) to (c) may be used incombination. When materials are used in combination, they may be amixture of two or more materials selected from among any of groups (a)to (c), or they may be a mixture of two or more materials selected fromamong two or more of groups (a) to (c).

From the viewpoint of low cost and high adsorption properties, theinorganic ion adsorbent may contain aluminum sulfate-added activatedalumina.

From the viewpoint of inorganic ion adsorption properties and productioncost, the inorganic ion adsorbent is more preferably one having a metalelement other than M and N in solid solution in addition to the metaloxide represented by formula (1).

For example, it may be one with iron in solid solution with hydratedzirconium oxide represented by ZrO₂·mH₂O (where m is a numerical valueother than 0).

Examples of salts of polyvalent metals include hydrotalcite-basedcompounds represented by the following formula (2):M²⁺ _((1-p))M³⁺ _(p)(OH⁻)(_(2+p−q))(A^(n−))_(q/r)  (2){where M²⁺ is at least one divalent metal ion selected from the groupconsisting of Mg²⁺, Ni²⁺, Zn²⁺, Fe²⁺, Ca²⁺ and Cu²⁺, M³⁺ is at least onetrivalent metal ion selected from the group consisting of Al³⁺ and Fe³⁺,A^(n−) is an n-valent anion, 0.1≤p≤0.5, 0.1≤q≤0.5, and r is 1 or 2}.

A hydrotalcite-based compound represented by formula (2) is preferredbecause it is inexpensive as an inorganic ion adsorbent and has highadsorption properties.

Examples of insoluble hydrous oxides include insoluble heteropolyacidsalts and insoluble hexacyanoferrates.

Metal carbonates have excellent performance from the standpoint ofadsorption properties, but from the standpoint of elution, the purposeof use must be considered when carbonates are to be used as inorganicion adsorbents.

From the viewpoint of allowing ion-exchange reaction with the carbonateion, the metal carbonate may include at least one type of metalcarbonate represented by the following formula (3):QyRz(CO₃)s·tH₂O  (3){where y is 1 or 2, Z is 0 or 1, s is 1 to 3, t is 0 to 8, and Q and Rare metal elements selected from the group consisting of Mg, Ca, Sr, Ba,Sc, Mn, Fe, Co, Ni, Ag, Zn, Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho,Er, Tm, Yb and Lu and are different from each other}.

The metal carbonate may be a non-water-containing (non-hydrated) metalcarbonate where tin formula (3) is 0, or it may be a hydrate where t isa numerical value other than 0.

From the viewpoint of low elution and excellent adsorption propertiesfor phosphorus, boron, fluorine and/or arsenic, the inorganic ionadsorbent is preferably selected from among the following group (d):

(d) magnesium carbonate, calcium carbonate, strontium carbonate, bariumcarbonate, scandium carbonate, manganese carbonate, iron carbonate,cobalt carbonate, nickel carbonate, silver carbonate, zinc carbonate,yttrium carbonate, lanthanum carbonate, cerium carbonate, praseodymiumcarbonate, neodymium carbonate, samarium carbonate, europium carbonate,gadolinium carbonate, terbium carbonate, dysprosium carbonate, holmiumcarbonate, erbium carbonate, thulium carbonate, ytterbium carbonate andlutetium carbonate.

Because elution of the metal carbonate or recrystallization of inorganicions and metal ions on the metal carbonate are expected as mechanisms ofadsorption of inorganic ions by the metal carbonate, a metal carbonatewith higher solubility is expected to have higher inorganic ionadsorption and more excellent adsorption performance. Metal elution fromthe inorganic ion adsorbent is also a concern, and therefore carefulstudy is necessary for uses where metal elution may be problem.

The inorganic ion adsorbent composing the porous molded body of theembodiment may also contain contaminating impurity elements that arepresent due to the production process, in ranges that do not interferewith functioning of the porous molded body. Examples of potentiallycontaminating impurity elements include nitrogen (in the form of nitricacid, nitrous acid or ammonium), sodium, magnesium, sulfur, chlorine,potassium, calcium, copper, zinc, bromine, barium and hafnium.

The inorganic ion adsorbent composing the porous molded body of theembodiment may also contain contaminating impurity elements that arepresent due to the production process, in ranges that do not interferewith functioning of the porous molded body. Examples of potentiallycontaminating impurity elements include nitrogen (in the form of nitricacid, nitrous acid or ammonium), sodium, magnesium, sulfur, chlorine,potassium, calcium, copper, zinc, bromine, barium and hafnium.

The method of replacement to organic liquid is not particularlyrestricted, and it may be centrifugal separation and filtration afterdispersing the water-containing inorganic ion adsorbent in an organicliquid, or passage of an organic liquid after filtration with a filterpress. For a higher replacement rate, it is preferred to repeat a methodof filtration after dispersion of the inorganic ion adsorbent in anorganic liquid.

The replacement rate of water to organic liquid during production may be50 mass % to 100 mass %, preferably 70 mass % to 100 mass % and morepreferably 80 mass % to 100 mass %.

The organic liquid replacement rate is the value represented by thefollowing formula (4):Sb=100−Wc  (4)where Sb (mass %) is the replacement rate to organic liquid and We (mass%) is the moisture content of the filtrate after treating thewater-containing inorganic ion adsorbent with the organic liquid.

The moisture content of the filtrate after treatment with the organicliquid can be determined by measurement by the Karl Fischer method.

Drying after replacement of the water in the inorganic ion adsorbentwith organic liquid can inhibit aggregation during drying, can increasethe pore volume of the inorganic ion adsorbent and can increase theadsorption capacity.

If the replacement rate of the organic liquid is less than 50 mass %,the aggregation suppressing effect during drying will be reduced and thepore volume of the inorganic ion adsorbent will not increase.

[Removal of Microparticles]

The blood purification device of the embodiment can be safely used eventhough the porous molded body contains an inorganic ion adsorbent.Specifically, the concentrations of Mg, Al, Ti, V, Cr, Mn, Fe, Ni, Cu,Zn, Ga, Rb, Sr, Y, Zr, Mo, Ru, Ag, Cd, Sn, Cs, La, Pr, Sm, Gd, Tb, Ta,Au, Tl, Co, In and Bi are all 0.1 ppb or lower and the concentration ofBa, Nd and Pb is 1 ppb or lower, in the saline solution at 3 months and6 months after the physiological saline for injection has beenencapsulated in the blood purification device. The blood purificationdevice of the embodiment conforms to the approval standards forartificial kidney devices established by the Ministry of Health, Labourand Welfare, described below. Specifically, in the blood purificationdevice of the embodiment, the number of microparticles with sizes of 10μm or greater is no more than 25 and the number of microparticles withsizes of 25 μm or greater is no more than 3, in 1 mL of thephysiological saline for injection at 3 months and 6 months after thephysiological saline for injection has been encapsulated in the bloodpurification device, while the absorbance of an eluate test solution is0.1 or lower, and the test solution does not contain a membrane poreretainer.

The present inventors have found that even though the porous molded bodycontains an inorganic ion adsorbent when the blood purification deviceof the embodiment is produced, microparticles generated by the bloodpurification device can be completely removed if it is washed with asupercritical fluid or subcritical fluid.

A supercritical fluid is a fluid in a state above the critical pressure(hereunder also referred to as “Pc”) and above the critical temperature(hereunder also referred to as “Tc”). A subcritical fluid is a fluid ina state other than a supercritical state, with conditions of0.5<P/Pc<1.0 and 0.5<T/Tc, or 0.5<P/Pc and 0.5<T/Tc<1.0, where thepressure and temperature during reaction are denoted by P and T,respectively. The preferred ranges for the pressure and temperature ofthe subcritical fluid are 0.6<P/Pc<1.0 and 0.6<T/Tc, or 0.6<P/Pc and0.6<T/Tc<1.0. When the fluid is water, the ranges for the temperatureand pressure for a subcritical fluid may be 0.5<P/Pc<1.0 and 0.5<T/Tc,or 0.5<P/Pc and 0.5<T/Tc<1.0. The temperature is represented as degreesCelsius, but the formula representing the subcritical state does notapply if either Tc or T is a negative value.

The supercritical fluid or subcritical fluid used may be water or anorganic medium such as alcohol, or a gas such as carbon dioxide,nitrogen, oxygen, helium, argon or air, or a mixed fluid comprisingthem. Carbon dioxide is most preferred because it allows a supercriticalstate to be achieved at nearly ordinary temperature, so that variousdifferent substances can be thoroughly dissolved.

[Porous Molded Body-Forming Polymer]

A porous molded body-forming polymer capable of forming a porous moldedbody to be used in the blood purification device of the embodiment maybe any polymer capable of forming a porous molded body, examples ofwhich include various types such as polysulfone-based polymers,polyvinylidene fluoride-based polymers, polyvinylidene chloride-basedpolymers, acrylonitrile-based polymers, polymethyl methacrylate-basedpolymers, polyamide-based polymers, polyimide-based polymers, cellulosicpolymers, ethylene-vinyl alcohol copolymer-based polymers, polyarylether sulfones, polypropylene-based polymers, polystyrene-based polymersand polycarbonate-based polymers. Among these, aromatic polysulfones arepreferred for excellent thermostability, acid resistance, alkaliresistance and mechanical strength.

Aromatic polysulfones to be used for the embodiment include those havingrepeating units represented by the following formula (5):—O—Ar—C(CH₃)₂—Ar—O—Ar—SO₂—Ar—  (5){where Ar is a disubstituted phenyl group at the para position} or thefollowing formula (6):—O—Ar—SO₂—Ar—  (6){where Ar is a disubstituted phenyl group at the para position}. Thepolymerization degree and molecular weight of the aromatic polysulfoneare not particularly restricted.[Hydrophilic Polymer]

A hydrophilic polymer used to form the porous molded body of theembodiment is not particularly restricted so long as it is abiocompatible polymer that swells but does not dissolve in water, andexamples include polymers having one or more sulfonic acid, carboxyl,carbonyl, ester, amino, amide, cyano, hydroxyl, methoxy, phosphate,oxyethylene, imino, imide, iminoether, pyridine, pyrrolidone, imidazoleor quaternary ammonium groups.

When the porous molded body-forming polymer is an aromatic polysulfone,a polyvinylpyrrolidone (hereunder also referred to as “PVP”)-basedpolymer is most preferred as the hydrophilic polymer.

Polyvinylpyrrolidone-based polymers include vinylpyrrolidone-vinylacetate copolymer, vinylpyrrolidone-vinylcaprolactam copolymer andvinylpyrrolidone-vinyl alcohol copolymer, and preferably at least one ofthese is used. From the viewpoint of compatibility with thepolysulfone-based polymer, the most suitable ones for use arepolyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer andvinylpyrrolidone-vinylcaprolactam copolymer.

The porous molded body to be used in the blood purification device ofthe embodiment is preferably coated with a biocompatible polymer, thebiocompatible polymer preferably being selected from the groupconsisting of polymethoxyethyl acrylate (PMEA) and polyvinylpyrrolidone(PVP)-based polymers.

[Polymethoxyethyl Acrylate (PMEA)]

The biocompatibility (blood compatibility) of PMEA is described indetail in “Artificial organ surface-biocompatibilizing materials”,Tanaka, K., BIO INDUSTRY, Vol 20, No. 12, 59-70 2003.

This article describes preparing PMEA, and an acrylate-based polymerwith a different side chain structure for comparison, and evaluatingplatelets, leukocytes, complement and coagulation markers duringcirculation of blood, and it is stated that “the PMEA surface had minoractivation of blood components compared to other polymers, while thePMEA surface had excellent blood compatibility due to a significantlylow level of human platelet adhesion and low morphological changes inthe adhered platelets”.

Presumably, therefore, PMEA has good blood compatibility not simplybecause it is hydrophilic due to ester groups in the structure, butrather the state of water molecules adsorbed onto the surface also has amajor effect on its blood compatibility.

It is known that in the ATR-IR method, waves impinging on a sample arereflected after entering into the sample to a small degree, such thatinfrared absorption in the region of the entering depth can be measured,but the present inventors have found that the region of measurement inthe ATR-IR method is essentially equal to the depth of the “surfacelayer” that corresponds to the surface of the porous molded body. Thatis, it was found that the blood compatibility in a region atapproximately equal depth as the ATR-IR measurement region governs theblood compatibility of the porous molded body, and that the presence ofPMEA in that region can provide a blood purification device withconsistent blood compatibility. If the surface of the porous molded bodyis coated with PMEA, then generation of microparticles from the bloodpurification device after long-term storage can also be inhibited.

The measuring region by ATR-IR depends on the wavelength and incidentangle of infrared light in air, the refractive index of the prism andthe refractive index of the sample, but it will usually be a region ofwithin 1 μm from the surface.

The presence of PMEA on the surface of the porous molded body can beconfirmed by thermal decomposition gas chromatography-mass spectrometryof the porous molded body. The presence of PMEA is estimated using thepeak near 1735 cm⁻¹ on the infrared absorption curve from totalreflection infrared absorption (ATR-IR) measurement of the surface ofthe porous molded body, although neighboring peaks can arise due toother substances. Thermal decomposition gas chromatography-massspectrometry may therefore be performed to confirm the presence of PMEA,by confirming PMEA-derived 2-methoxyethanol.

PMEA has a characteristic solubility in solvents. For example, PMEA doesnot dissolve in a 100% ethanol solvent but has a range of solubility ina water/ethanol mixed solvent, depending on the mixing ratio. If themixing ratio is in the soluble range, the peak intensity of thePMEA-attributed peak (near 1735 cm⁻¹) is higher with a larger amount ofwater.

For a porous molded body comprising PMEA on the surface, the variationin water permeability is minimal and product design is simpler, due tolower variation in pore sizes on the surface. The porous molded body ofthis embodiment has PMEA on the surface, but when the PMEA has beencoated onto the porous molded body it is assumed that the PMEA adheresas an ultra-thin film, coating the porous molded body surfaceessentially without blocking the pores. PMEA is especially preferredbecause of its small molecular weight and short molecular chains, whichmakes it less likely to form a thick coating film structure or to alterthe structure of the porous molded body. PMEA is also preferred becauseit has high compatibility with other substances, allowing it to beevenly coated onto the porous molded body surface and helping to improvethe blood compatibility.

The weight-average molecular weight of the PMEA can be measured by gelpermeation chromatography (GPC), for example.

The method of forming a PMEA coating layer on the surface of the porousmolded body may be a method of coating by flowing a PMEA-dissolvedcoating solution from the top of a column (vessel) packed with theporous molded body.

[Polyvinylpyrrolidone (PVP)-Based Polymer]

The polyvinylpyrrolidone (PVP)-based polymer is not particularlyrestricted, but polyvinylpyrrolidone (PVP) is suitable for use.

[Number of Microparticles, Eluted Metal Concentration]

A blood purification device that is to be applied for dialysis mustconform to the approval standards for artificial kidney devicesestablished by the Ministry of Health, Labour and Welfare, in order toobtain approval for production as a dialysis-type (afferent) artificialkidney device. The blood purification device of the embodiment musttherefore conform to the eluting material test criteria listed in theapproval standards for artificial kidney devices. In the bloodpurification device of the embodiment, the number of microparticles withsizes of 10 μm or greater is no more than 25 in 1 mL of saline solutionand the number of microparticles with sizes of 25 μm or greater is nomore than 3 in 1 mL of saline solution, at 3 months and 6 months afterthe physiological saline for injection has been encapsulated in theblood purification device, while the absorbance of the eluate testsolution is 0.1 or lower.

For the same reason, in the blood purification device of the embodiment,the concentrations of Mg, Al, Ti, V, Cr, Mn, Fe, Ni, Cu, Zn, Ga, Rb, Sr,Y, Zr, Mo, Ru, Ag, Cd, Sn, Cs, La, Pr, Sm, Gd, Tb, Ta, Au, Tl, Co, Inand Bi are all 0.1 ppb or lower and the concentration of Ba, Nd, Pb andCe is 1 ppb or lower, in the saline solution at 3 months and 6 monthsafter the physiological saline for injection has been encapsulated inthe blood purification device.

The measuring methods for the number of microparticles and Mg, Al, Ti,V, Cr, Mn, Fe, Ni, Cu, Zn, Ga, Rb, Sr, Y, Zr, Mo, Ru, Ag, Cd, Sn, Cs,La, Pr, Sm, Gd, Tb, Ta, Au, Tl, Co, In, Bi, Ba, Nd, Pb and Ce in thephysiological saline for injection encapsulated in the bloodpurification device are as follows.

(1) Measuring Method for Wet-Type Blood Purification Device

A wet-type blood purification device encapsulates a solution (such as UFfiltration membrane water) just before shipping and is subjected toradiation sterilization in the solution and then shipped. In a wet-typeblood purification device, after the solution has been completelyremoved and after the porous molded body in the blood purificationdevice has been flushed with 10 L of physiological saline for injection(or after filtering from the membrane inner surface side to the membraneouter surface side if the porous molded body is a hollow fibermembrane), fresh physiological saline for injection is encapsulated, andthen the mixture is incubated at 25° C.±1° C. and stored in a stationarystate for 3 months. Sampling of the saline solution from the bloodpurification device is carried out after removing as much of thesolution (filled solution) as possible from the blood purificationdevice and then uniformly mixing. For example, after sampling formeasurement at 3 months, the remaining saline solution is placed in theoriginal blood purification device and sealed, stored for an additional3 months, and used for measurement at 6 months.

(2) Measuring Method for Dry-Type Blood Purification Device

Radiation sterilization is usually not carried out in solution with adry-type blood purification device, and it is usually shipped in a drystate. After the porous molded body in the blood purification device hasbeen flushed with 10 L of physiological saline for injection (or afterfiltering from the membrane inner surface side to the membrane outersurface side if the porous molded body is a hollow fiber membrane),fresh physiological saline for injection is encapsulated, and then themixture is incubated at 25° C.±1° C. and stored in a stationary statefor 3 months. Sampling of the saline solution from the bloodpurification device is carried out after removing as much of thesolution (filled solution) as possible from the blood purificationdevice and then uniformly mixing. For example, after sampling formeasurement at 3 months, the remaining saline solution is placed in theoriginal blood purification device and sealed, stored for an additional3 months, and used for measurement at 6 months.

The number of microparticles in the sampled solution (or filledsolution) can be measured with a particle counter.

[Phosphorus Adsorption Performance of Porous Molded Body]

The porous molded body of the embodiment can be suitably used foradsorption of phosphorus during hemodialysis of a dialysis patient. Thecomposition of blood is categorized into blood plasma components andblood cell components, with the blood plasma components comprising 91%water, 7% proteins, and lipid components and inorganic salts, and withphosphorus in the blood being present as phosphate ions among the bloodplasma components. The blood cell components are composed of 96%erythrocytes, 3% leukocytes and 1% platelets, the sizes of erythrocytesbeing 7 to 8 μm in diameter, the sizes of leukocytes being 5 to 20 μm indiameter and the sizes of platelets being 2 to 3 μm in diameter.

Since the most common pore size of a porous molded body measured by amercury porosimeter is 0.08 to 0.70 μm, and consequently the abundanceof the inorganic ion adsorbent on the outer surface is high, this allowsphosphorus ions to be reliably adsorbed even by high-speed liquid flowtreatment, and also allows excellent penetration, diffusion andadsorption of phosphorus ions into the porous molded body. There is alsono reduction in blood flow by clogging with blood cell components.

For this embodiment, the surface of the porous molded body has abiocompatible polymer, allowing it to be used as a more suitablephosphorus adsorbent for blood treatment.

If the device comprises a porous molded body with the most common poresize being 0.08 to 0.70 μm and the surface of the porous molded body hasa biocompatible polymer, then phosphorus ions in blood will beselectively and reliably adsorbed, so that the phosphorus concentrationin blood returning to the body will be nearly 0. By returningessentially phosphorus-free blood to the body, presumably phosphoruswill more actively move into the blood from intracellular orextracellular regions, for a greater refilling effect.

By inducing a refilling effect that supplements phosphorus in the blood,it may even be possible to eliminate phosphorus present in extracellularfluid or in cells, which normally cannot be eliminated.

Thus, phosphorus levels in the blood of a dialysis patient can beproperly managed without taking oral phosphorus adsorbents, or by takingonly small amounts (auxiliary usage), thus avoiding side-effects indialysis patients.

A blood purification device having a porous molded body packed into avessel (column) may be used during dialysis in connection with adialyzer, either in series before and after or in parallel with it. Theblood purification device of the embodiment can be used as a bloodpurification device for adsorption of phosphorus, and has excellentselectivity and adsorption performance for inorganic phosphorus evenwith a low phosphorus level in the blood and a high space velocity.

From the viewpoint of helping to induce a refilling effect, preferablythe blood purification device of the embodiment is used in connectionbefore and after the dialyzer.

From the viewpoint of allowing a refilling effect to be obtained, thephosphorus adsorption rate (%) (the proportion of blood phosphorus thatis absorbed) is preferably 50% or higher, more preferably 60% or higher,and most suitably 70% or higher, 80% or higher, 85% or higher, 90% orhigher, 95% or higher or 99% or higher.

There are no limitations on the material of the vessel (column) of theblood purification device of the embodiment, and examples are mixedresins such as polystyrene-based polymers, polysulfone-based polymers,polyethylene-based polymers, polypropylene-based polymers,polycarbonate-based polymers and styrene-butadiene blocked copolymers. Apolyethylene-based polymer or polypropylene-based polymer is preferablyused from the viewpoint of material cost.

[Method for Producing Porous Molded Body]

The method for producing a porous molded body of the embodiment will nowbe described in detail.

The method for producing a porous molded body of the embodimentincludes, for example, (1) a step of drying an inorganic ion adsorbent,(2) a step of pulverizing the inorganic ion adsorbent obtained in step(1), (3) a step of mixing the inorganic ion adsorbent obtained in step(2), a good solvent for the porous molded body-forming polymer, a porousmolded body-forming polymer and, depending on the case, a hydrophilicpolymer (water-soluble polymer) to prepare a slurry, (4) a step ofmolding the slurry obtained in step (3), and (5) a step of coagulatingthe molded article obtained in step (4) in a poor solvent.

[Step (1): Inorganic Ion Adsorbent Drying Step]

In step (1), the inorganic ion adsorbent is dried to obtain a powder. Inorder to inhibit aggregation during the drying, preferably the dryingduring production is carried out after replacing the moisture with anorganic liquid. The organic liquid is not particularly restricted solong as it has an effect of inhibiting aggregation of the inorganic ionadsorbent, but it is preferred to use a liquid with high hydrophilicity.Examples include alcohols, ketones, esters and ethers.

The replacement rate to the organic liquid may be 50 mass % to 100 mass%, preferably 70 mass % to 100 mass % and more preferably 80 mass % to100 mass %.

The method of replacement to organic liquid is not particularlyrestricted, and it may be centrifugal separation and filtration afterdispersing the water-containing inorganic ion adsorbent in an organicliquid, or passage of an organic liquid after filtration with a filterpress. For a higher replacement rate, it is preferred to repeat a methodof filtration after dispersion of the inorganic ion adsorbent in anorganic liquid.

The replacement rate to the organic liquid can be determined bymeasurement of the filtrate moisture content by the Karl Fischer method.

Drying after replacement of the water in the inorganic ion adsorbentwith organic liquid can inhibit aggregation during drying, can increasethe pore volume of the inorganic ion adsorbent and can increase theadsorption capacity.

If the replacement rate of the organic liquid is less than 50 mass %,the aggregation suppressing effect during drying will be reduced and thepore volume of the inorganic ion adsorbent will not increase.

[Step (2): Inorganic Ion Adsorbent Pulverizing Step]

In step (2), the inorganic ion adsorbent powder obtained from step (1)is pulverized. The pulverizing method is not particularly restricted,and may be dry grinding or wet grinding.

A dry grinding method is not particularly restricted, and it may be oneemploying an impact crusher such as a hammer mill, an airflow pulverizersuch as a jet mill, a medium pulverizer such as a ball mill or acompression pulverizer such as a roller mill.

An airflow pulverizer is preferred among these because it can create asharp particle size distribution of the pulverized inorganic ionadsorbent.

A wet grinding method is not particularly restricted so long as itallows pulverizing and mixing together of the inorganic ion adsorbentand the good solvent for the porous molded body-forming polymer, and itmay employ means used in physical pulverizing methods such aspressurized disruption, mechanical grinding or ultrasonic treatment.

Specific examples of pulverizing and mixing means include blenders suchas generator shaft homogenizers and Waring blenders, medium agitationmills such as sand mills, ball mills, attritors and bead mills, and jetmills, mortar/pestle combinations, kneaders and sonicators.

A medium agitation mill is preferred for high pulverizing efficiency andto allow pulverizing to a highly viscous state.

The ball diameter used in a medium agitation mill is not particularlyrestricted but is preferably 0.1 mm to 10 mm. If the ball diameter is0.1 mm or greater, the ball mass will be sufficient to providepulverizing force and high pulverizing efficiency, while a ball diameterof 10 mm or smaller will result in excellent fine pulverizing power.

The material of the ball used in a medium agitation mill is notparticularly restricted, and it may be a metal such as iron or stainlesssteel, or a ceramic which is an oxide such as alumina or zirconia or anon-oxide such as silicon nitride or silicon carbide. Zirconia issuperior among these for its excellent abrasion resistance, and from theviewpoint of low contamination (wear contamination) into products.

After pulverizing, a filter or the like is preferably used forfiltration purification with the inorganic ion adsorbent in a fullydispersed state in the good solvent for the porous molded body-formingpolymer.

The particle size of the pulverized and purified inorganic ion adsorbentis 0.001 to 10 μm, preferably 0.001 to 2 μm and more preferably 0.01 to0.1 μm. A smaller particle size is more favorable for uniformlydispersing the inorganic ion adsorbent in the membrane-forming solution.It tends to be difficult to produce uniform microparticles with sizes ofsmaller than 0.001 μm. With an inorganic ion adsorbent exceeding 10 μm,it tends to be difficult to stably produce a porous molded body.

[Step (3): Slurry Preparation Step]

In step (3), the inorganic ion adsorbent obtained in step (2), a goodsolvent for the porous molded body-forming polymer, a porous moldedbody-forming polymer and, depending on the case, a water-soluble polymer(hydrophilic polymer) are mixed to prepare a slurry.

The good solvent for the porous molded body-forming polymer used in step(2) and step (3) is not particularly restricted so long as it stablydissolves the porous molded body-forming polymer at greater than 1 mass% under the production conditions for the porous molded body, and anyconventionally known one may be used.

Examples of good solvents include N-methyl-2-pyrrolidone (NMP),N,N-dimethylacetamide (DMAC) and N,N-dimethylformamide (DMF).

The good solvent used may be a single one alone, or two or more may beused in admixture.

The amount of porous molded body-forming polymer added in step (3) maybe such that the proportion of porous molded body-formingpolymer/(porous molded body-forming polymer+water-soluble polymer+goodsolvent for porous molded body-forming polymer) is preferably 3 mass %to 40 mass % and more preferably 4 mass % to 30 mass %. If the porousmolded body-forming polymer content is 3 mass % or greater a porousmolded body with high strength can be obtained, and if it is 40 mass %or lower a porous molded body with high porosity can be obtained.

While addition of a water-soluble polymer is not absolutely necessary instep (3), addition can yield a homogeneous porous molded body comprisinga filamentous structure that forms a three-dimensional connected networkstructure on the outer surface and interior of the porous molded body,or in other words, a porous molded body can be obtained with easier poresize control and reliable ion adsorption even with high-speed liquidflow treatment.

The water-soluble polymer used in step (3) is not particularlyrestricted so long as it is compatible with the good solvent for theporous molded body-forming polymer, and with the porous moldedbody-forming polymer.

A natural polymer, semisynthetic polymer or synthetic polymer may beused as the water-soluble polymer.

Examples of natural polymers include guar gum, locust bean gum,carrageenan, gum arabic, tragacanth, pectin, starch, dextrin, gelatin,casein and collagen.

Examples of semisynthetic polymers include methyl cellulose, ethylcellulose, hydroxyethyl cellulose, ethylhydroxyethyl cellulose,carboxymethyl starch and methyl starch.

Examples of synthetic polymers include polyvinyl alcohol,polyvinylpyrrolidone (PVP), polyvinyl methyl ether, carboxyvinylpolymer, sodium polyacrylate, and polyethylene glycols such astetraethylene glycol and triethylene glycol.

A synthetic polymer is preferred from the viewpoint of increasing theloading capacity of the inorganic ion adsorbent, whilepolyvinylpyrrolidone (PVP) or a polyethylene glycol is preferred fromthe viewpoint of increasing the porosity.

The weight-average molecular weight of the polyvinylpyrrolidone (PVP) orpolyethylene glycol is preferably 400 to 35,000,000, more preferably1,000 to 1,000,000 and even more preferably 2,000 to 100,000.

If the weight-average molecular weight is 400 or greater, a porousmolded body with high surface openness will be obtained, and if it is35,000,000 or lower, the viscosity of the slurry during molding will below, tending to facilitate the molding.

The weight-average molecular weight of the water-soluble polymer can bemeasured by dissolving the water-soluble polymer in a predeterminedsolvent and analyzing it by gel permeation chromatography (GPC).

The amount of water-soluble polymer added may be such that theproportion of water-soluble polymer/(water-soluble polymer+porous moldedbody-forming polymer+good solvent for porous molded body-formingpolymer) is preferably 0.1 mass % to 40 mass %, more preferably 0.1 mass% to 30 mass % and even more preferably 0.1 mass % to 10 mass %.

If the amount of water-soluble polymer added is 0.1 mass % or greater,it will be possible to uniformly obtain a porous molded body thatincludes a filamentous structure forming a network structure that isthree-dimensionally connected on the outer surface and interior of theporous molded body. If the amount of water-soluble polymer added is 40mass % or lower, the open area ratio on the outer surface will besatisfactory and the abundance of the inorganic ion adsorbent on theouter surface of the porous molded body will be high, to obtain a porousmolded body that can reliably adsorb ions even with high-speed liquidflow treatment.

[Step (4): Molding Step]

In step (4), the slurry obtained in step (3) (molding slurry) is molded.The molding slurry is a mixed slurry comprising the porous moldedbody-forming polymer, the good solvent for the porous moldedbody-forming polymer, the inorganic ion adsorbent and if necessary awater-soluble polymer.

The form of the porous molded body of the embodiment may be any desiredform such as particulate, filamentous, sheet-like, hollow fiber-like,cylindrical or hollow cylindrical, depending on the method of moldingthe molding slurry.

There are no particular restrictions on the method of molding aparticulate form, such as spherical particles, and for example, it maybe a rotation nozzle method in which the molding slurry housed in avessel is ejected from nozzles provided on the side wall of the rotatingvessel to form droplets. The rotating nozzle method allows molding intoa particulate form with a uniform particle size distribution.

More specifically, the method may be atomization of the molding slurryfrom single-fluid or double-fluid nozzles for coagulation in acoagulating bath.

The nozzle diameters are preferably 0.1 mm to 10 mm and more preferably0.1 mm to 5 mm. The droplets will be more easily ejected if the nozzlediameters are at least 0.1 mm, and the particle size distribution can bemade uniform if it is 10 mm or smaller.

The centrifugal force is represented as the centrifugal acceleration,and it is preferably 5 G to 1500 G, more preferably 10 G to 1000 G andeven more preferably 10 G to 800 G.

If the centrifugal acceleration is 5 G or greater the formation andejection of the droplets will be facilitated, and if it is 1500 G orlower the molding slurry will be discharged without becomingfilamentous, and widening of the particle size distribution can beinhibited. A narrow particle size distribution will result in uniformwater flow channels when the porous molded body is packed into thecolumn, providing an advantage whereby even when ultra high-speed waterflow treatment is used there is no leakage of ions (the target ofadsorption) from the start of water flow.

A method of molding into a filamentous or sheet form may be a method ofextruding the molding slurry from a spinneret or die having that shape,and coagulating it in a poor solvent.

A method of molding into a hollow fiber porous molded body may bemolding in the same manner as a method of molding the porous molded bodyinto a filamentous or sheet form, but using a spinneret with an annularorifice.

A method of molding the porous molded body into a cylindrical or hollowcylindrical form, when extruding the molding slurry from a spinneret,may be cutting while coagulating in a poor solvent, or coagulating intoa filamentous form followed by cutting.

[Step (5): Coagulation Step]

In step (5), the molded article with accelerated coagulation obtained instep (4) is further coagulated in a poor solvent to obtain a porousmolded body.

<Poor Solvent>

The poor solvent for step (5) may be a solvent with a solubility of 1mass % or lower for the porous molded body-forming polymer under theconditions in step (5), and examples include water, alcohols such asmethanol and ethanol, ethers, and aliphatic hydrocarbons such asn-hexane and n-heptane. Water is most preferred as the poor solvent.

In step (5), the good solvent is carried over from the preceding steps,causing variation in the concentration of the good solvent at the startand end points of the coagulation step. The poor solvent may thereforehave the good solvent added beforehand, and preferably the coagulationstep is carried out while managing the concentration by separateaddition of water or the like so as to maintain the initialconcentration.

By adjusting the concentration of the good solvent it is possible tocontrol the structure (the outer surface open area ratio and particleshapes) of the porous molded body.

When the poor solvent is water or a mixture of water with the goodsolvent for the porous molded body-forming polymer, the content of thegood solvent for the porous molded body-forming polymer with respect tothe water in the coagulation step is preferably 0 to 80 mass % and morepreferably 0 to 60 mass %.

If the content of the good solvent for the porous molded body-formingpolymer is 80 mass % or lower, a favorable effect for a satisfactoryporous molded body shape will be obtained.

The temperature of the poor solvent is preferably 40 to 100° C., morepreferably 50 to 100° C. and even more preferably 60 to 100° C., fromthe viewpoint of controlling the temperature and humidity of the spacesin the rotating vessel that causes ejection of the droplets bycentrifugal force, as described below.

[Production Apparatus for Porous Molded Body]

When the porous molded body of the embodiment is in particulate form,the production apparatus comprises a rotating vessel that ejectsdroplets by centrifugal force and a coagulation tank that stores acoagulating solution, also optionally being provided with a cover thatcovers the space between the rotating vessel and the coagulation tankand comprising control means that controls the temperature and humidityin the space.

The rotating vessel that ejects droplets by centrifugal force is notrestricted to one with a specific construction so long as it has thefunction of ejecting the molding slurry as spherical droplets bycentrifugal force, and examples include known types of rotating discs orrotating nozzles.

With a rotating disc, the molding slurry is supplied to the center ofthe rotating disc and the molding slurry is developed into a film ofuniform thickness along the surface of the rotating disc, and thendivided into droplets by centrifugal force from the peripheral edges ofthe disc to eject the microdroplets.

A rotating nozzle either has a plurality of through-holes formed in theperimeter wall of a rotating vessel having a hollow disc shape, or ithas nozzles attached through the perimeter wall, with the molding slurrybeing supplied into the rotating vessel while rotating the rotatingvessel, and the molding slurry being discharged by centrifugal forcefrom the through-holes or nozzles to form droplets.

The coagulation tank that stores the coagulating solution is not limitedto any particular structure so long as it has a function allowing it tostore the coagulating solution, and for example, it may be a coagulationtank with an open top side, as is commonly known, or a coagulation tankhaving a construction in which the coagulating solution is allowed toflow down naturally by gravity along the inner walls of the cylindersituated surrounding the rotating vessel.

A coagulation tank with an open top side is an apparatus that allowsdroplets ejected in the horizontal direction from the rotating vessel tofall down naturally, and traps droplets on the liquid surface of thecoagulating solution stored in the open-top coagulation tank.

A coagulation tank with a construction in which the coagulating solutionis allowed to flow down naturally by gravity along the inner walls ofthe cylinder surrounding the rotating vessel is an apparatus thatdischarges the coagulating solution at a roughly equivalent flow rate inthe circumferential direction along the inner walls of the cylinder, andtraps droplets in the coagulating solution flowing downward along theinner walls, causing them to coagulate.

The control means for the temperature and humidity in the space isprovided with a cover that covers the space between the rotating vesseland coagulation tank, and it controls the temperature and humidity inthe space.

The cover covering the space is not restricted to any particularconstruction so long as it has the function of isolating the space fromthe external environment and facilitating practical control of thetemperature and humidity in the space, and it may be box-shaped, tubularor umbrella-shaped, for example.

The material of the cover may be stainless steel metal or plastic, forexample. For isolation from the external environment, it may also becovered by a known type of insulation. The cover may also be partiallyprovided with openings for temperature and humidity adjustment.

The means for controlling the temperature and humidity in the space isnot limited to any particular means so long as it has the function ofcontrolling the temperature and humidity in the space, and for example,it may be a heating machine such as an electric heater or steam heater,or a humidifier such as an ultrasonic humidifier or heating humidifier.

A preferred means in terms of construction is one that heats thecoagulating solution stored in the coagulation tank and utilizes steamgenerated from the coagulating solution to control the temperature andhumidity in the space.

A method of forming a coating layer of a biocompatible polymer on thesurface of a porous molded body will now be described.

For this embodiment, a coating solution containing a PMEA- or aPVP-based polymer, for example, may be applied onto the surface of theporous molded body to form a coating film. For example, a PMEA coatingsolution can penetrate the pores formed in the porous molded body,allowing the PMEA to be added to the entire pore surface of the porousmolded body without significantly altering the pore sizes on the surfaceof the porous molded article.

The solvent of the PMEA coating solution is not particularly restrictedso long as it is a solvent that can dissolve or disperse the PMEAwithout dissolving the polymers such as the porous molded body-formingpolymer of the porous molded body and the water-soluble polymer, but itis preferably water or an aqueous alcohol solution, for process safetyand satisfactory handleability in the subsequent drying step. From theviewpoint of the boiling point and of toxicity, it is preferred to usewater, an aqueous ethanol solution, an aqueous methanol solution or anaqueous isopropyl alcohol solution.

The solvent of the PVP coating solution is not particularly restrictedso long as it is a solvent that can dissolve or disperse the PVP withoutdissolving the polymers such as the porous molded body-forming polymerof the porous molded body and the water-soluble polymer, but it ispreferably water or an aqueous alcohol solution, for process safety andsatisfactory handleability in the subsequent drying step. From theviewpoint of the boiling point and of toxicity, it is preferred to usewater, an aqueous ethanol solution, an aqueous methanol solution or anaqueous isopropyl alcohol solution.

The type and composition of the solvent in the coating solution isselected as appropriate in relation to the polymer forming the porousmolded body.

The PMEA concentration of the PMEA coating solution is not restricted,but as an example it may be 0.001 mass % to 1 mass %, and preferably0.005 mass % to 0.2 mass %, of the coating solution.

The method of applying the coating solution is also not restricted, andan example is a method in which the porous molded body is packed into asuitable column (vessel) and flushed from the top with a coatingsolution containing PMEA, and compressed air is then used to remove theexcess solution.

After subsequently washing with distilled water and substituting out theunnecessary solvent, it may be sterilized for use as a medical tool.

EXAMPLES

Examples and Comparative Examples will now be described, with theunderstanding that they are not limitative on the invention. Thephysical properties of the porous molded body and the performance of theblood purification device were measured as follows. The scope of theinvention is not limited to the Examples described below, and variousmodifications may be implemented within the scope of the gist thereof.

[Metal Concentration Analysis]

The metal concentration in the physiological saline for injection wasmeasured before encapsulation in the blood purification device and uponremoval 3 months and 6 months after encapsulation, using an inductivelycoupled plasma mass spectrometer (iCAPQ by ThermoSCIENTIFIC). The amountof metal elution was the difference compared to the amount of metal inthe physiological saline for injection before injection into the bloodpurification device.

[Mean Particle Size of Porous Molded Body and Mean Particle Size ofInorganic Ion Adsorbent]

The mean particle size of the porous molded body and the mean particlesize of the inorganic ion adsorbent were measured using a laserdiffraction/scattering particle size distribution analyzer (LA-950,trade name of Horiba Co.). The dispersing medium used was water. Formeasurement of samples using hydrated cerium oxide as the inorganic ionadsorbent, the refractive index used was the value for cerium oxide.Likewise, for measurement of samples using hydrated zirconium oxide asthe inorganic ion adsorbent, the refractive index used was the value forzirconium oxide.

[Phosphorus Adsorption with Bovine Plasma]

The apparatus shown in FIG. 1 was used to measure the phosphorusadsorption by a column flow test with low-phosphorus serum using bovineplasma. Bovine plasma prepared to a low phosphorus level (0.7 mg/dL) wasused for measurement of the amount of phosphorus adsorbed by the porousmolded body (mg-P/mL-resin (porous molded body)) packed into a column(vessel) under conditions equivalent to common dialysis conditions(space velocity SV=120, 4 hours dialysis).

The phosphate ion concentration was measured by the molybdic acid directmethod.

Phosphorus adsorption of 1.5 (mg-P/mL-resin) or greater with a flowspeed of SV120 was judged to be high adsorption capacity andsatisfactory as a phosphorus adsorbent.

[Amount of Microparticles]

A microparticle counter (KL-04 by Rion Co., Ltd.) was used formeasurement of each evaluation sample. After discarding the firstmeasured value, measurement was performed an additional 3 times and theaverage was recorded as the measured value.

Example 1

After loading 2000 g of cerium sulfate tetrahydrate (Wako Pure ChemicalIndustries, Ltd.) in 50 L of purified water, a stirring blade was usedfor dissolution, and then 3 L of 8 M caustic soda (Wako Pure ChemicalIndustries, Ltd.) was added dropwise at a rate of 20 ml/min to obtain ahydrated cerium oxide precipitate. The obtained precipitate was filteredwith a filter press and then washed by flowing through 500 L of purifiedwater, after which 80 L of ethanol (Wako Pure Chemical Industries, Ltd.)was additionally flowed through, replacing the water in the hydratedcerium oxide with ethanol. A 10 ml portion of the filtrate was sampledafter filtration was complete, and the moisture content was measuredwith a Karl Fischer moisture content meter (CA-200, trade name ofMitsubishi Chemical Holdings Corp. Analytech Co., Ltd.), resulting in amoisture content of 5 mass % and an organic liquid replacement rate of95 mass %. The hydrated cerium oxide containing the organic liquid wasair dried to obtain dried hydrated cerium oxide.

The obtained dried hydrated cerium oxide was pulverized using a jet millapparatus (SJ-100, trade name of Nisshin Engineering Inc.) underconditions with a pneumatic pressure of 0.8 MPa and a starting materialfeed rate of 100 g/hr, to obtain hydrated helium oxide powder having amean particle size of 1.2 μm.

After adding 214.8 g of N-methyl-2-pyrrolidone (NMP, product ofMitsubishi Chemical Corp.), 146.4 g of pulverized hydrated cerium oxidepowder (MOX) and 39.2 g of polyethersulfone (PES, product of SumitomoChemical Co., Ltd.), the mixture was heated to 60° C. in a dissolutiontank and stirred to dissolution using a stirring blade, to obtain ahomogeneous molding slurry solution.

The obtained molding slurry was supplied into a cylindrical rotatingvessel with 4 mm-diameter nozzles opened in the side wall, and thevessel was rotated to form droplets from the nozzles by centrifugalforce (15 G). The droplets were allowed to splash into a coagulationtank with an open top side storing a coagulating solution with an NMPcontent of 50 mass % with respect to water, that had been heated to 60°C., to coagulate the molding slurry.

Alkali cleaning and sorting were also carried out after ethanolreplacement, to obtain a spherical porous molded body.

The particle size of the porous molded body was 537 μm, the bulk densitywas 0.45 g/ml-resin and the water content was 83.2%.

[Washing with Supercritical Fluid]

The obtained porous molded body was washed for 1 hour using asupercritical fluid comprising carbon dioxide (critical temperature:304.1K, critical pressure: 7.38 MPa, device by ITEC Co., Ltd.).

[PMEA Coating]

A 1 mL portion of the obtained porous molded body was packed into acylindrical vessel (having a glass filter set at the base, L (length)/D(cylinder diameter)=1.5). Next, 0.2 g of PMEA (Mn 20,000, Mw/Mn 2.4) wasdissolved in an aqueous solution of 40 g ethanol/60 g water (100 g) toprepare a coating solution. The vessel packed with the porous moldedbody was held vertically and flushed from the top with the coatingsolution at a flow rate of 100 mL/min, contacting the coating solutionwith the porous molded body, after which it was washed with purifiedwater.

After the purified water washing, the coating solution was sprayed intothe vessel with air at 0.1 MPa, the module was placed in a vacuum dryerand vacuum dried for 15 hours at 35° C., and gamma sterilization wascarried out at 25 kGy in an air atmosphere to fabricate a bloodpurification device.

[Column Flow Test with Low-Phosphorus Serum using Bovine Plasma]

Considering the intended use as a phosphorus adsorber after use of adialyzer in dialysis treatment, it was decided to measure the phosphorusadsorption at a dialyzer outlet during dialysis treatment, with aninorganic phosphorus concentration of 0.2 to 1.0 mg/dl in blood. Thephosphorus concentration in the test plasma solution was thereforeadjusted.

Commercially available bovine serum was centrifuged (3500 rpm, 5 min)and 2000 mL of blood plasma supernatant was prepared. The phosphorusconcentration in the blood plasma was 10.8 mg/dL.

The porous molded body obtained in Example 1 was added to half of theobtained blood plasma (1000 mL), and stirred for 2 hours at roomtemperature, after which it was centrifuged (3500 rpm, 5 min) to obtainapproximately 950 mL of blood plasma with a phosphorus concentration of0.

After mixing 35 mL of blood plasma with a phosphorus concentration of10.8 mg/dL and 465 mL of blood plasma with a phosphorus concentration of0, the mixture was centrifuged (3500 rpm, 5 min) to obtain 495 mL ofblood plasma with a phosphorus concentration of 0.8 mg/dL, assupernatant.

The blood purification device obtained in Example 1 was incorporated asshown in FIG. 1 , and 450 mL of the obtained blood plasma was flowedthrough at a flow rate of 2 mL/min, sampling 10 mL as the first fractionand 20 mL for each sample thereafter. Based on usual average dialysisconditions of 4 hours of dialysis at a flow rate Qb=200 mL/min, thetotal blood flow was 200 mL×4 hours=48,000 mL, and assuming the bloodcell component to be Ht=30%, the blood plasma flow was 33,600 mL. Theamount of liquid flow was 340 mL in this case, since the experiment wasat a 1/100 scale.

The phosphorus adsorption of the porous molded body at a blood plasmaflow volume of 350 mL was 2.91 mg-P/mL-resin.

[Evaluation Results]

The performance of the obtained blood purification device is shown inTable 1. The blood purification device had high phosphorus adsorptioncapacity, was safely usable, and its number of microparticles and metalelution conformed to the approval standards for artificial kidneydevices.

Example 2

After adding 217.6 g of NMP and 31.6 g of PES to 31.6 g ofpolyvinylpyrrolidone (PVP, K90 by BASF Corp.) as the hydrophilic polymer(water-soluble polymer) and 119.2 g of MOX, the same procedure wascarried out as in Example 1 to obtain a spherical porous molded body.

The performance of the obtained blood purification device is shown inTable 1. The blood purification device had high phosphorus adsorptioncapacity, was safely usable, and its number of microparticles and metalelution conformed to the approval standards for artificial kidneydevices.

Example 3

A blood purification device was fabricated in the same manner as Example1, except that PMEA was not coated. The performance of the obtainedblood purification device is shown in Table 1.

Comparative Example 1

A blood purification device was fabricated in the same manner as Example1, except that washing with a supercritical fluid was not carried out.The properties of the obtained blood purification device are shown inTable 1.

Comparative Example 2

A blood purification device was fabricated in the same manner as Example1, except that alkali cleaning was not carried out after coagulation ofthe molding slurry. The properties of the obtained blood purificationdevice are shown in Table 1.

TABLE 1 Example Example Example Comparative Comparative Construction 1 23 Example 1 Example 2 Porous molded body-forming polymer/weight (wt %)PES/9.8 PES/7.9 PES/9.8 PES/9.8 PES/9.8 Water-soluble polymer/weight (wt%) — PVP/7.9 — — — Inorganic ion adsorbent/weight (wt %) Ce/36.6 Ce/29.8Ce/36.6 Ce/36.6 Ce/36.6 Solvent/weight (wt %) NMP/53.7 NMP/54.4 NMP/53.7NMP/53.7 NMP/53.7 Particle size of inorganic ion adsorbent (μm) 1.2 1.21.2 1.2 1.2 Concentration of Mg, Al, Ti, V, Cr, Mn, Ni, Cu, Zn, Ga, <0.1<0.1 <0.1 <0.1 0.2 Rb, Sr, Y, Zr, Mo, Ru, Ag, Cd, Sn, Cs, La, Pr, Sm,Gd, Tb, Ta, Au, Tl, Co, In, Bi (ppb) Fe concentration (ppb) <0.1 <0.1<0.1 <0.1 20 Ba, Nd, Pb concentration (ppb) <1 <1 <1 <1 3 Ceconcentration (ppb) <1 <1 <1 <1 9 Particle size (μm) 537 543 537 538 537Blood phosphorus adsorption (mg/ml-resin) 2.91 3.94 2.91 2.88 2.95*Granulatable Yes Yes Yes Yes Yes Number of microparticles ≥10 μm[number] 5 2 5 20 5 after elapse of 1 week ≥25 μm [number] 0 0 1 3 0Number of microparticles ≥10 μm [number] 8 4 10 30 9 after elapse of 3months ≥25 μm [number] 1 1 2 8 1 Number of microparticles ≥10 μm[number] 9 6 16 66 12 after elapse of 6 months ≥25 μm [number] 2 1 3 102 *Granulatable: Judged whether spherical shapes can be obtained duringgranulation.

Example 4

A blood purification device was fabricated in the same manner as Example2, except that for PMEA coating, 1.0 g of PMEA was dissolved in anaqueous solution of 40 g methanol/60 g water (100 g) to prepare acoating solution, and washing with a supercritical fluid was not carriedout. The performance of the obtained blood purification device is shownin Table 2. The blood purification device had high phosphorus adsorptioncapacity, was safely usable, and its number of microparticles and metalelution conformed to the approval standards for artificial kidneydevices.

Example 5

A blood purification device was fabricated in the same manner as Example2, except that hydrated zirconium oxide (R Zirconium Hydroxide, tradename of Daiichi Kigenso Kagaku Kogyo Co., Ltd.) was used instead of MOX.The performance of the obtained blood purification device is shown inTable 2. The blood purification device had high phosphorus adsorptioncapacity, was safely usable, and its number of microparticles and metalelution conformed to the approval standards for artificial kidneydevices.

Example 6

A blood purification device was fabricated in the same manner as Example2, except that lanthanum oxide (product of Nacalai Tesque, Inc.) wasused instead of MOX. The performance of the obtained blood purificationdevice is shown in Table 2. The blood purification device had highphosphorus adsorption capacity, was safely usable, and its number ofmicroparticles and metal elution conformed to the approval standards forartificial kidney devices.

Example 7

A blood purification device was fabricated in the same manner as Example2, except that neodymium carbonate (Neodymium Carbonate Octahydrate,trade name of Fujifilm Wako Chemical Corp.) was used instead of MOX. Theperformance of the obtained blood purification device is shown in Table2. The blood purification device had high phosphorus adsorptioncapacity, was safely usable, and its number of microparticles and metalelution conformed to the approval standards for artificial kidneydevices.

Example 8

A blood purification device was fabricated in the same manner as Example1, except that the molding slurry solution used was a mixed solutioncomprising 220 g of NMP, 200 g of MOX, 4 g of PVP, and 10 g of acopolymer with limiting viscosity [η]=1.2 (organic polymer resin, PAN),comprising 91.5 wt % acrylonitrile, 8.0 wt % methyl acrylate and 0.5 wt% sodium methacrylsulfonate. The performance of the obtained bloodpurification device is shown in Table 2. The blood purification devicehad high phosphorus adsorption capacity, was safely usable, and itsnumber of microparticles and metal elution conformed to the approvalstandards for artificial kidney devices.

Example 9

A blood purification device was fabricated in the same manner as Example1, except that the molding slurry solution used was a mixed solutioncomprising 160 g of dimethyl sulfoxide (DMSO, product of Kanto KagakuCo., Ltd.) as the good solvent for the organic polymer resin, 20 g ofethylene-vinyl alcohol copolymer (EVOH, SOARNOL E3803, trade name ofNippon Synthetic Chemical Industry Co., Ltd.) as the organic polymerresin, 4 g of PVP and 200 g of MOX. The performance of the obtainedblood purification device is shown in Table 2. The blood purificationdevice had high phosphorus adsorption capacity, was safely usable, andits number of microparticles and metal elution conformed to the approvalstandards for artificial kidney devices.

Example 10

A blood purification device was fabricated in the same manner as Example1, except that the molding slurry solution used was a mixed solutioncomprising 220 g of DMSO, 28 g of poly(methyl methacrylate) (PMMA,DIANAL BR-77, trade name of Mitsubishi Chemical Corp.) as the organicpolymer resin, 32 g of PVP and 120 g of MOX. The performance of theobtained blood purification device is shown in Table 2. The bloodpurification device had high phosphorus adsorption capacity, was safelyusable, and its number of microparticles and metal elution conformed tothe approval standards for artificial kidney devices.

TABLE 2 Example Example Example Example Example Example ExampleConstruction 4 5 6 7 8 9 10 Porous molded body-forming polymer/weight(wt %) PES/7.9 PES/7.9 PES/7.9 PES/7.9 PAN/2.3 EVOH/5.2 PMMA/7.0Water-soluble polymer/weight (wt %) PVP/7.9 PVP/7.9 PVP/7.9 PVP/7.9PVP/0.9 PVP/1.0 PVP/8.0 Inorganic ion adsorbent/weight (wt %) Ce/29.8Zr/29.8 La/29.8 Nd/29.8 Ce/46.1 Ce/52.1 Ce/30.0 Solvent/weight (wt %)NMP/54.4 NMP/54.4 NMP/54.4 NMP/54.4 NMP/50.7 DMSO/41.7 DMSO/55.0Particle size of inorganic ion adsorbent (μm) 1.2 1.2 1.2 1.2 1.2 1.21.2 Concentration of Mg, Al, Ti, V, Cr, Mn, Ni, Cu, Zn, Ga, <0.1 <0.1<0.1 <0.1 <0.1 <0.1 <0.1 Rb, Sr, Y, Zr, Mo, Ru, Ag, Cd, Sn, Cs, La, Pr,Sm, Gd, Tb, Ta, Au, Tl, Co, In, Bi (ppb) Fe concentration (ppb) <0.1<0.1 <0.1 <0.1 <0.1 <0.1 <0.1 Ba, Nd, Pb concentration (ppb) <1 <1 <1 <1<1 <1 <1 Ce concentration (ppb) <1 <1 <1 <1 <1 <1 <1 Particle size (μm)539 536 533 535 371 533 537 Blood phosphorus adsorption (mg/ml-resin)1.80 1.92 9.88 9.17 2.30 1.64 1.54 *Granulatable Yes Yes Yes Yes Yes YesYes Number of microparticles ≥10 μm [number] 22 2 8 13 2 4 6 afterelapse of 1 week ≤25 μm [number] 2 0 2 3 0 0 1 Number of microparticles≥10 μm [number] 23 3 9 16 2 4 8 after elapse of 3 months ≤25 μm [number]2 0 3 3 0 0 1 Number of microparticles ≥10 μm [number] 24 3 10 19 2 4 8after elapse of 6 months ≤25 μm [number] 3 1 3 3 0 0 1 *Granulatable:Judged whether spherical shapes can be obtained during granulation.

INDUSTRIAL APPLICABILITY

Since the blood purification device of the invention has high phosphorusadsorption capacity and safe usability, it can be suitably used intherapy for periodic removal of phosphorus that has accumulated in thebody.

REFERENCE SIGNS LIST

-   -   1 Thermostatic bath    -   2 Laboratory bench    -   3 Pump    -   4 Column containing porous absorber (phosphorus absorbent)    -   5 Pressure gauge    -   6 Sampling

The invention claimed is:
 1. A blood purification device comprising a porous molded body that includes an inorganic ion adsorbent, wherein the concentrations of Mg, Al, Ti, V, Cr, Mn, Fe, Ni, Cu, Zn, Ga, Rb, Sr, Y, Zr, Mo, Ru, Ag, Cd, Sn, Cs, La, Pr, Sm, Gd, Tb, Ta, Au, Tl, Co, In and Bi are all 0.1 ppb or lower and the concentrations of Ba, Nd, Pb and Ce are all 1 ppb or lower, in physiological saline for injection in the blood purification device at 3 months and 6 months after opening the physiological saline for injection, while the number of microparticles with sizes of 10 μm or greater is no more than 25 and the number of microparticles with sizes of 25 μm or greater is no more than 3, in 1 mL of the physiological saline for injection at 3 months and 6 months after the same physiological saline for injection has been encapsulated in the blood purification device, wherein the porous molded body is coated with a first biocompatible polymer of polymethoxyethyl acrylate (PMEA), and wherein the blood purification device is prepared by washing the porous molded body with a supercritical fluid or subcritical fluid to remove microparticles and trace metals.
 2. The blood purification device according to claim 1, wherein the porous molded body is composed of a porous molded body-forming polymer, a hydrophilic polymer and an inorganic ion adsorbent.
 3. The blood purification device according to claim 2, wherein the porous molded body-forming polymer is an aromatic polysulfone.
 4. The blood purification device according to claim 2 or 3, wherein the hydrophilic polymer is a second biocompatible polymer.
 5. The blood purification device according to claim 4, wherein the second biocompatible polymer is a polyvinylpyrrolidone (PVP)-based polymer.
 6. The blood purification device according to claim 1 or 2, wherein the inorganic ion adsorbent contains at least one metal oxide represented by the following formula (1): MN_(x)O_(n) ·mH₂O  (1) wherein x is 0 to 3, n is 1 to 4, m is 0 to 6, and M and N are metal elements selected from the group consisting of Ti, Zr, Sn, Sc, Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Al, Si, Cr, Co, Ga, Fe, Mn, Ni, V, Ge, Nb and Ta, and are different from each other.
 7. The blood purification device according to claim 6, wherein the metal oxide is selected from among the following groups (a) to (c): (a) hydrated titanium oxide, hydrated zirconium oxide, hydrated tin oxide, hydrated cerium oxide, hydrated lanthanum oxide and hydrated yttrium oxide; (b) complex metal oxides comprising at least one metal element selected from the group consisting of titanium, zirconium, tin, cerium, lanthanum, neodymium and yttrium and at least one metal element selected from the group consisting of aluminum, silicon and iron; and (c) activated alumina.
 8. A method for producing the blood purification device according to claim 1, comprising a step of washing the porous molded body containing the inorganic ion adsorbent with a supercritical fluid or subcritical fluid, and then coating the surface with PMEA. 